EP1147108B1 - Derives heterocycliques d'azote substitue et leur utilisation pharmaceutique - Google Patents

Derives heterocycliques d'azote substitue et leur utilisation pharmaceutique Download PDF

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EP1147108B1
EP1147108B1 EP00901478A EP00901478A EP1147108B1 EP 1147108 B1 EP1147108 B1 EP 1147108B1 EP 00901478 A EP00901478 A EP 00901478A EP 00901478 A EP00901478 A EP 00901478A EP 1147108 B1 EP1147108 B1 EP 1147108B1
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group
alkyl
substituted
carbon atoms
formula
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EP1147108A1 (fr
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Jan Hanus
Vladimir; Krystof
Marián HAJDUCH
Jaroslav Vesely
Miroslav Strnad
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Institute of Experimental Botany Academy CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • This invention relates to new purine and pyrazolopyrimidine derivatives and their deaza analogues and to their use in suitable utilities, especially diagnostic and therapeutic methods.
  • cdks cyclin-dependent kinase proteins
  • Purine analogues as cdk inhibitors are disclosed for example in WO 97/16452, WO 98/05335 and WO/9720842. The teaching of these patents includes 2,6,9-trisubstituted and less substituted purine derivatives only.
  • Tetrasubstituted purines are disclosed in WO 98/01448 in which substituents are short hydrocarbonyl chains, usually represented by hydrogen.
  • Substituents at C6 represents hydrogen or amine optionally substituted by one or two hydrocarbon groups; substituents at C8 are hydroxy, mercapto, acyloxy or oxycarbonyl substituted by aliphatic alkyl only.
  • Nucleotide analogues containing phosphonate groups are diclosed for example in U.S.
  • Typical purine base is adenine, 2,6-diaminopurine and guanine.
  • the purine bases may include the deaza analogues thereof.
  • the invention concerns substituted nitrogen heterocyclic derivatives of the formula I wherein,
  • halogen refers to fluorine, bromine, chlorine, and iodine atoms
  • alkyl refers to
  • the invention concerns further substituted nitrogen heterocyclic derivatives of the formula Ib , wherein R2, R6, R8 and R9 have above mentioned meanings.
  • the invention concerns further substituted nitrogen heterocyclic derivatives of the formula I selected from the group consisting of 2-(1-hydroxymethylpropylamino)-6-benzylamino-8-chloro (or hydroxy, bromo, fluoro, amino, amido, carboxy, cyano, methylamino, thio, methylthio, ⁇ -hydroxyalkylamino, ⁇ -hydroxyalkyloxy, ⁇ -carboxyalkylamino, ⁇ -aminoalkylamino, ⁇ -fosfonoalkylamino, ⁇ -fosfonoalkyloxy, propinyl)-9-isopropylpurine, 2-(2-aminopropylamino)-6-benzylamino-8-chloro (or hydroxy, bromo, fluoro, amino, amido, carboxy, cyano, methylamino, thio, methylthio, ⁇ -hydroxyalkylamino, ⁇ -hydroxyalky
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives of formula I, wherein R2, R6, R8 and R9 have above mentioned meanings, A is a group of formula and Z is N, characterized in that a trisubstituted derivative of formula XI , wherein R2, R6 and R9 have above mentioned meanings, is brominated with using a brominating system selected from a group consisting of bromine/acetic acid, bromine/chloroform, bromine/acetate buffer, bromine/water, N-bromosuccinimide/dimethylformamide and bromoacetamide/dimethylformamide to obtain a derivative of formula XIa , wherein R2, R6 and R9 have above mentioned meanings, and the bromine atom in position 8 of the derivative of formula XIa is then optionally subjected to a substitution in order to replace it by another substituent R8, which has above mentioned meanings.
  • a brominating system selected from a group consisting of bro
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives of formula I , wherein R2, R6, R8 and R9 have above mentioned meanings, A is a group of formula and Z is N, characterized in that a trisubstituted derivative of formula XIb , wherein R6 and R9 have above mentioned meanings, is brominated with using a brominating system selected from a group consisting of bromine/acetic acid, bromine/chloroform, bromine/acetate buffer, bromine/water, N-bromosuccinimide/dimethylformamide and bromoacetamide/dimethylformamide to obtain a derivative of formula XIc , wherein R6 and R9 have above mentioned meanings, and the chlorine atom in position 2 and the bromine atom in position 8 of the derivative of formula XIc are optionally, either progressively or simultaneously, subjected to a nucleophilic substitution in order to replace them by another substituents R2 and R8, that have above mentioned
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives of formula I, wherein R2, R6 and R8 have above mentioned meanings, R9 is alkyl as defined above, A is a group of formula and Z is N, characterized in that, a trisubstituted derivative of formula XIIa , wherein R6 is as defined above, is alkylated in position 9 with using an appropriate alkylating agent in a system selected from a group consisting of K 2 CO 3 /dimethylformamide, Cs 2 CO 3 /dimethylformamide, t-BuOK/dimethylformamide, t-BuOK/dimethylsulphoxide and NaH/dimethylformamide or under conditions of Mitsunobu reaction to obtain a derivative of formula XIIb wherein R6 and alkyl are as defined above, and the chlorine atoms in positions 2 and 8 of the derivative of formula XIIb are optionally, either progressively or simultaneously, subjected to a substitution
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives, wherein R2, R6 and R8 have above mentioned meanings, R9 is alkyl as defined above, A is a group of formula and Z is N, characterized in that a trisubstituted derivative of formula XIIa, wherein R6 has above mentioned meanings, is protected by reacting, for example, with 2-dihydropyrane/H + to obtain a derivative of formula XIIc, wherein R6 has above mentioned meanings, and a group R6 and/or the chlorine atom in position 2 and/or the chlorine atom in position 8 are optionally converted to another substituents R2, R6 and R8, that have above mentioned meanings and in such optionally modificated product of formula XIIc, the 2-tetrahydropyranyl group is split off to obtain a corresponding derivative of formula XIIc wherein R9 is hydrogen, and so obtained product is then alkylated in position 9 with using an appropriate alkylating
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives of formula I, wherein R2, R6 and R8 have above mentioned meanings, R9 is alkyl as defined above, A is a group and Z is N, characterized in that, 2,6,8-trichloropurine is subjected to a nucleophilic substitution in position 6 in order to replace the chlorine atom in position 6 by another substituent R6 as defined above to obtain a derivative of formula XIIa, wherein R6 has above mentioned meanings, and so obtained product is then alkylated in position 9 with using an appropriate alkylating agent in a system selected from a group consisting of K 2 CO 3 /dimethylformamide, Cs 2 CO 3 /dimethylformamide, t-BuOK/dimethylformamide, t-BuOK/dimethylsulphoxide and NaH/dimethylformamide or under conditions of Mitsunobu reaction to obtain a derivative of formula XIIb, wherein R6 and al
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives of formula I, wherein R2, R6 and R8 have above mentioned meanings, R9 is alkyl as defined above, A is a group of formula and Z is N, characterized in that 2,6-dichloropurine is subjected to a nucleophilic substitution in position 6 in order to replace the chlorine atom in position 6 by another substituent R6 as defined above, and so obtained derivative of formula XVII, wherein R6 is as defined above, is alkylated in position 9 with using either methyl acrylate or acrylonitrile or oxirane to obtain a derivative of formula XVIIa wherein R6 and alkyl have above mentioned meanings, which product is then brominated in position 8 with using a brominating system selected from a group consisting of bromine/acetic acid, bromine/chloroform, bromine/acetate buffer, bromine/water, N-bromosuccinimide/dimethylformamide and bromo
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives of formula I, wherein R6 is a halogen, R2, R8 and R9 have above mentioned meanings, A is a group of formula and Z is N, characterized in that a derivative of formula XVIII , wherein R2, R8 and R9 have above mentioned meanings, is halogenated via diazotation with using, for example, amylnitrite/CH 2 Br 2 or amylnitrite/CHI 3 .
  • the invention also relates to a method for preparing substituted nitrogen heterocyclic derivatives of formula I, wherein R9 has above mentioned meanings and one substituent of R2, R6 or R8 is alkinyl or alkenyl containing 1 to 6 carbon atoms whereas two other substituents of R2, R6 and R8 have above mentioned meanings, A is a group of formula and Z is N, characterized in that a derivative of formula I , wherein R9 has above mentioned meanings and one substituent of R2, R6 and R8 is a halogen whereas two other substituents of R2, R6 and R8 have above mentioned meanings, is alkinylated in the position of the halogen with using alkine/triphenylphosphine-PdCl 2 /CuI/triethylamine system and so obtained 2-, 6- or 8-alkinyl derivative is optionally converted to 2-, 6- or 8-alkenyl derivative with using a Lindlar catalyst.
  • the invention also relates to substituted nitrogen heterocyclic derivatives of formula I and pharmaceutically acceptable salts thereof for use as medicaments.
  • the invention also relates to substituted nitrogen heterocyclic derivatives of formula I for use as means for preparing affinity adsorption matrices, immobilized enzymes for process control, immunoassay reagents, diagnostic samples, 14 C-, 3 H-, avidin- or biotin-labelled compounds, oligonucleotides and diagnostic samples.
  • the invention also relates to substituted nitrogen heterocyclic derivatives of formula I for use as antimitotic drugs, in particular drugs for elimination or reduction of viral spread or growth in tissue culture systems during the production of biopharmaceutical or other products such as proteins and vaccines, drugs for elimination or reduction of viral spread and growth in clinical samples such as blood, and drugs for stopping of growth of tissue culture cells while leaving the cells to carry on with protein production.
  • the invention also relates to a pharmaceutical composition with cytostatic, anticancer, antimitotic, antineurodegenerative, immunosuppressive and antimicrobial activity, characterised in that it comprises, in addition to auxiliary pharmaceutical matters, at least one substituted nitrogen heterocyclic derivative of formula I .
  • the invention also relates to a combined pharmaceutical composition with cytostatic effect, characterised in that it comprises, in addition to auxiliary pharmaceutical matters, a combination of at least one substituted nitrogen heterocyclic derivative of formula I and a cytostatic agent selected from a group consisting of mitoxantron, cis- and carbo-platin, methotrexate, taxol and doxorubicin.
  • a cytostatic agent selected from a group consisting of mitoxantron, cis- and carbo-platin, methotrexate, taxol and doxorubicin.
  • the invention also relates to a use of substituted nitrogen heterocyclic derivatives of formula I for preparing medicaments destined for treating tumours, cancers, psoriasis, rheumatoid arthritis, lupus, type I diabetes, multiple sclerosis, restenosis, polycyclic kidney disease, host graft disease and gout, parasitoses, such as those caused by fungi or prostis, or Alzheimer's disease, or for preparing antineurodegenerative drugs and suppress immunostimulation agents.
  • novel compounds of this invention have a wide variety of diagnostic, therapeutic and industrial utilities.
  • the compounds of this invention are suitable as intermediates for use in the preparation of affinity absorption matrices.
  • the phosphonate groups in matrix bound form are useful in the chromatographic separation of positively charged molecules.
  • Other immobilised examples of the compounds herein are useful in purifying proteins, e.g., cell cycle enzymes (cdk's), enzymes involved in recognition of the compound of this invention, e.g. transport proteins.
  • cdk's cell cycle enzymes
  • Suitable methods of incorporation of the compounds of this invention into polymeric resins will be readily apparent to the skilled artisan, for instance the compounds are incorporated by cross-linking hydroxyl groups of the phosphonate or hydroxymethyl substituents using cross-linking agents heretofore known. Linking through a group other than the heterocyclic base will produce a resin useful in hydrophobic affinity chromatography.
  • Other suitable linking methods are described in Cihiar (supra).
  • the compounds of the formula I and their pharmaceutically acceptable salts inhibit selectively the enzyme p34 cdc2 /cyclin B kinase and related cdks (cdk2, cdk5, cdk7, erk1, erk2).
  • this invention is a method for inhibiting cdks and cell proliferation in mammals comprising administering a therapeutically effective amount of the composition of claim 1 to the mammal.
  • the cdk inhibiting molecules are useful for treating cell proliferation disorders such as rheumatoid arthritis. lupus, type I diabetes, multiple sclerosis, cancer, restenosis, Alzheimer's disease, growth of parazites (animal, protists), host graft disease, and gout.
  • this invention is a composition useful for treating fungal infections (fungi) in humans, animal, and in plants.
  • this kinase controls certain steps of cell division cycles, in particular the transition from G1 phase into the S phase and in particular the transition from the G2 phase into the M phase.
  • hypoproliferative diseases such as cancer, restenosis and Alzheimer's disease.
  • they are capable of inhibiting cell cycle transitions (G1/S, G2/M, M-phase/metaphase) carried out on the different animal bodies and embryos.
  • the compounds are useful in treating autoimune diseases, e.g.
  • rheumatoidal arthritis in treating of cancer, cardiovascular disease such as restenosis, host vs graft disease, gout, polycystic kidney disease and other proliferative diseases whose pathogenesis involves abnormal cell proliferation.
  • This invention also concerns novel compounds that have been discovered to be potent and specific inhibitors of I ⁇ B- ⁇ kinase which prevents signal induced NF- ⁇ B activation and cytokine synthesis in vitro and in vivo .
  • Such inhibitors are expected to inhibit synthesis of cytokines and adhesion proteins whose synthesis is transcriptionally regulated by NF- ⁇ B.
  • Pro-inflammatory cytokines such as IL-1, IL-6, TNF and adhesion proteins (e.g. ICAM, VCAM and selections) belong to this class of molecules and have implicated in the pathogenesis of inflammatory diseases.
  • a potent inhibitor of I ⁇ B- ⁇ kinase is useful in the clinical management of diseases where the NF- ⁇ B activation is required for disease induction.
  • p53 the mammal cell's own natural brake gene for stopping uncontrolled cell proliferation (cancer), thus being able to switch off the cancer.
  • p53 as well as retinoblastoma (Rb) are two well-characterised tumour suppressors whose inactivation may led to uncontrolled cell proliferation and malignancy. Phosphorylation of these two proteins, which are involved in the cell cycle regulatory mechanisms, is known to modulate their function.
  • a potent cdk inhibitor represent a good toll for treatment of cancers due to induction of wild type p53 protein in cancers expressing mutant p53.
  • the interest is therefore assessed by application of the derivatives of the invention for stimulating on of p53-independent apoptosis in the cells, which have stopped at stage G2 through damage to the DNA using agents such as mitoxantrone or cis-platinum.
  • the cdk inhibitors of this invention can thus increase the therapeutic potential of the anti-tumour agents currently used.
  • the compounds of this invention will generally be terminally incorporated into the oligonucleotide. If they do not contain phosphonyl group attached to the hydroxyl group, they optionally are incorporated internally into the sequence of the oligonucleotide. Terminally incorporated diphosphonyl compounds of this invention which contain no free hydroxyl capable of participating in chain elongation also are useful in DNA sequencing in essentially the same manner as deoxyNTPs have been used in the past (see example 8 of U.S. Patent 5,276,143).
  • the nucleotide analogue is included in a kit with other reagents (such as Klenow polymerase or T4 polymerase, dNTPs, etc) needed for DNA sequencing (Otvos, et al. "Nucl. Acids.Res.” 15:1763-1777 (1987).
  • the oligonucleotide-incorporated compound of this invention is binding-competent for its complementary sequence, i.e., if it is capable of base pairing, then this nucleotide monomer will participate in hybridisation. It is not necessary, however, that the incorporated nucleotide analogue of this invention base pair or otherwise participate in hybridisation. If it is located at the terminus of the oligonucleotide it will be useful as an immunological recognition site, or haptenic recognition site, to facilitate detection of the oligonucleotide by an antibody capable of binding the compound of this invention.
  • the compounds of this invention also are useful as linkers or spacers in preparation affinity absorption matrices (as opposed to functioning as affinity moieties per se as noted above), immobilised enzymes for process control, or immunoassay reagents.
  • the compounds herein contain a multiplicity of functional groups that are suitable as sites for cross-linking desired substances. For example, it is conventional to link affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates. These insolubilised reagents are employed in known fashion to absorb binding partners for the affinity reagents from manufactured preparations, diagnostic samples and other impure mixture. Similarly, immobilised enzymes are used to perform catalytic conversions with facile recovery of enzyme. Bifunctional compounds are commonly used to link analytes to detectable groups in preparing diagnostic reagents.
  • the phosphonic acid is used to form esters with alcohols or amides with amines.
  • the R groups substituted with OH, azido (which is reduced to amino if desired before cross-linking) or vinyl are exemplary suitable sites.
  • the amino, halo, acyl and other reactive sites found on group B are suitable. Suitable protection of reactive groups will be used where necessary while assembling the cross-linked reagent.
  • the compounds here are used by linking them through phosphonic acid or amino group to the hydroxyl or amino groups of the linking partner in the same fashion as shown herein, and covalently bonded to the other binding partner through an R group.
  • a first binding partner such as a steroid hormone is esterified and then this conjugate is cross-linked through hydroxymethyl R to cyanogen bromide activated Sepharose, whereby immobilised steroid is obtained.
  • Other chemistries for conjugation are well known. See for example Maggio, “Enzyme-Immunoassay” (CRC, 1988, pp 71-135) and references cited therein.
  • the oligonucleotides of this invention are labelled with any conventional detectable label, e.g. a fluorescent moiety such a fluorescein, radioisotopes such as 14 C or 3 H, stable free radicals, avidin, biotin and the like all of which previously have been used as labels for immunoassays or diagnostic probes.
  • a fluorescent moiety such as fluorescein, radioisotopes such as 14 C or 3 H, stable free radicals, avidin, biotin and the like all of which previously have been used as labels for immunoassays or diagnostic probes.
  • the label will be present on the oligonucleotide or on the residue of an analogue of this invention. Suitable labelling methods are well known and are readily used with reactive groups such as hydroxyl, allyl and the like.
  • a simple method is to label the compound of this invention with H 3 by proton exchange.
  • the compounds also are biotinylated using conventional methods. See for instance U.S.
  • Patent 5,276,143 for analogous structures.
  • the compounds of this invention also are useful directly in diagnostic probe assays without an exogenous detectable label.
  • antibodies are raised against the compounds of this invention.
  • Such antibodies (which in turn are labelled or used in a double antibody configuration) bind to the analogue of this invention and thereby are useful in detecting its presence as label for a protein or oligonucleotide.
  • the compounds of the invention are useful for treatment of microbial infections, for treatment of tumours or for other indications described below.
  • Microbial infections treatable by the compounds of this invention include viruses, parasites, yeast and fungi; but it is believed that the compounds are most effective against viruses, which constitutes the preferred utility.
  • Exemplary viral infections include infections caused by DNA or RNA viruses including herpes viruses (CMV, HSV 1, HSV 2, EBV, varicella zoster virus (VZV), bovid herpesvirus type 1, equid herpesvirus type 1, HVV-6, papillomaviruses (HPV types 1-55 including carcinogenic HPV), flaviviruses (including yellow fever virus, African swine fever virus and Japanese encephalitis virus), togaviruses (including Venezuelan equine encephalomyelitis virus), influenza viruses (types A-C), retroviruses (HIV-1, HIV-2, HTLV-I, HTLV-II, SIV, FeLV, FIV, MoMSV), adenoviruses (types 1-8), poxviruses (vaccinia virus), enteroviruses (poliovirus types 1-3, Coxsackie, hepatitis A virus, and ECHO virus), gastroenteritis viruses (Norwalk viruses, rot
  • the antiviral activity of individual compounds is determined by routine assay of antiviral (or other antimicrobial) activity using enzyme inhibition assays, tissue culture assays, animal model assays and the like as will be understood by those skilled in the art.
  • protozoa include those members of the subphyla Sarcomastigophora and Sporozoa of the phylum Protozoa. More particularly, the term protozoa as used herein include genera of parazitic protozoa, which are important to man, because they either cause disease in man or in his domestic animals. These genera for the most part are classified in the superclass Mastigophora of the subphylum Sarcomastigophora and the class Telesporea of the subphylum Sporozoa in the classification according to Baker (1969).
  • Illustrative genera of these parasitic protozoa include Histomonas, Pneumocystis, Trypanosoma, Giardia, Trichomonas, Eimeria, Isopora, Leishmania, Entamoeba, Toxoplasma and Plasmodium.
  • Parasitic protozoans include Plasmodium falciparum, Plasmodium berghei, Plasmodium malariae, Plasmodium vivax, Leishmania braziliensis, Leishmania donovani, Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense, Pneumocystis carinii, Entamoeba histolytica, Trichomonas vaginalis and the like (de Vries, E., et al, "Mol. Biochem. Parasitol” 47:43-50 (1991) and trypanosomes (Kaminsky et al. "J.Parasitol.” 80(6): 1026-30 (1994).
  • the compounds in which R is CH 2 OH and B is 3-deazaadenine are particularly interesting in the treatment of malarial parasites.
  • Compounds of the invention are used to treat yeast or fungal infections caused by Candida glabrata, Candida ropicalis, Candida albicans , and other Candida species, Cryptococcus species including Cryptococcus neoformans, Blastomyces species including Blastomyces dermatidis, Torulopsis species including Torulopsis glabrata, Coccidioides species including Coccidioides immitis, Aspergillus species and the like.
  • the compounds of the invention can also be (1) applied to tissue culture systems to eliminate or reduce viral spread or growth during the production of biopharmaceutical or other products (such as proteins or vaccines), (2) used to eliminate or reduce viral spread or growth in clinical sample (such as blood), and (3) used to stop growth of tissue culture cells while leaving the cells to carry on with protein production.
  • biopharmaceutical or other products such as proteins or vaccines
  • clinical sample such as blood
  • the compounds herein have been found to suppress immunostimulation. Accordingly, they can suppress metabolic activities of T-lymphocytes stimulated by diverse agents, e.g. concavalin A, they principally will find application in the treatment of autoimmune diseases, e.g. arthritis, or in suppression of transplant rejection.
  • Their therapeutically active concentrations are in the range of 1 mg/kg to 50 mg/kg of body weight.
  • Suitable routes for administration include oral, rectal, vassal, topical (including ocular, buccal and sublingual), vaginal and parental (including subcutaneous, intramuscular, intravitreous, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration will depend upon the condition of the patient, the toxicity of the compound and the site of infection, among other considerations known to the clinician.
  • the therapeutical composition comprise about 1% to about 95% of the active ingredient, single-dose forms of administration preferably comprising about 20% to about 90% of the active ingredient and administration forms which are not single-dose preferably comprising about 5% to about 20% of the active ingredient.
  • Unit dose forms are, for example, coated tablets, tablets, ampoules, vials, suppositories or capsules.
  • Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions and the like. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.
  • compositions of the present invention are prepared in a manner known per se, for example by means of convential mixing, granulating, coating, dissolving or lyophilising processes.
  • solutions of the active ingredient, and in addition also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions are used, it being possible for these to be prepared before use, for example in the case of lyophilised compositions which comprise the active substance by itself or together with a carrier, for example mannitol.
  • the pharmaceutical compositions can be sterilised and/or comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilizing agents, salts for regulating the osmotic pressure and/or buffers, and they are prepared in a manner known per se, for example by means of convential dissolving or lyophilising processes.
  • the solutions or suspensions mentioned can comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Suspensions in oil comprise, as the oily component, the vegetable, synthetic or semisynthetic oils customary for injection purposes.
  • Oils which may be mentioned are, in particular, liquid fatty acid esters which contain, as the acid component, a long-chain fatty acid having 8 - 22, in particular 12-22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidinic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, euric acid, brasidic acid or linoleic acid, if appropriate with the addition of antioxidants, for example vitamin E, ( ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of these fatty acid esters has not more than 6 carbon atoms and is mono- or polyhydric, for example mono-, di- or trihydric alcohol, for example methanol, ethanol, propanol, butanol, or pentanol, or isomers thereof, but in particular glycol and glycerol.
  • Fatty acid esters are therefore, for example: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate from Gattefoseé, Paris), "Labrafil M 1944 CS” (unsaturated polyglycolated glycerides prepared by an alcoholysis of apricot kernel oil and made up of glycerides and polyethylene glycol esters; from Gattefoseé, Paris), “Labrasol” (saturated polyglycolated glycerides prepared by an alcoholysis of TCM and made up of glycerides and polyethylene glycol esters; from Gattefoseé, Paris) and/or "Miglyol 812" (triglyceride of saturated fatty acids of chain length C 8 to C 12 from Hüls AG, Germany), and in particular vegetable oils, such as cottonseed oil, almond oil, olive oil, cast
  • the preparation of the injection compositions is carried out in the customary manner under sterile conditions, as are bottling, for example in ampoules or vials, and closing of the containers.
  • compositions for oral use can be obtained by combining the active ingredient with one or more solid carriers, if appropriate granulating the resulting mixture, and, if desired, processing the mixture or granules to tablets or coated tablet cores, if appropriate by addition of additional excipients.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate, or calcium hydrogen phosphate, and furthermore binders, such as starches, for example maize, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and/or, if desired, desintegrators, such as the above mentioned starches, and furthermore carboxymethyl-starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates for example tricalcium phosphate, or calcium hydrogen phosphate
  • binders such as starches, for example maize,
  • Additional excipients are, in particular, flow regulators and lubricants, for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • flow regulators and lubricants for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Coated tablet cores ca be provided with suitable coatings which, if appropriate, are resistant to gastric juice, the coatings used being, inter alia, concentrated sugar solutions, which, if appropriate, comprise gum arabic, talc, polyvinylpyrrolidine, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings which are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be admixed to the tablets or coated tablet coatings, for example for identification or characterisation of different doses of active ingredient.
  • compositions which can be used orally, are also hard capsules of gelatin and soft, closed capsules of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the hard capsules can contain the active ingredient in the form of granules, mixed for example with fillers, such as maize starch, binders and/or lubricants, such as talc or magnesium stearate, and stabilisers if appropriate.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as greasy oils, parrafin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilisers and detergents, for example of the polyethylene sorbitan fatty acid ester type.
  • suitable liquid excipients such as greasy oils, parrafin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilisers and detergents, for example of the polyethylene sorbitan fatty acid ester type.
  • oral forms of administration are, for example, syrups prepared in the customary manner, which comprise the active ingredient, for example, in suspended form and in a concentration of about 5% to 20%, preferably about 10% or in a similar concentration which results in a suitable individual dose, for example, when 5 or 10 ml are measured out.
  • Other forms are, for example, also pulverulent or liquid concentrates for preparing of shakes, for example in milk. Such concentrates can also be packed in unit dose quantities.
  • compositions which can be used rectally, are, for example, suppositories that comprise a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, naturally occurring or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions which are suitable for parenteral administration are aqueous solutions of an active ingredient in water-soluble form, for example of water-soluble salt, or aqueous injection suspensions, which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate stabilisers.
  • the active ingredient can also be present here in the form of a lyophilisate, if appropriate together with excipients, and be dissolved before parenteral administration by addition of suitable solvents. Solutions such as are used, for example, for parental administration can also be used as infusion solutions. Preferred preservatives are, for example.
  • Antioxidants such as ascorbic acid, or microbicides, such as sorbic or benzoic acid.
  • Ointments are oil-in-water emulsions, which comprise not more than 70%, but preferably 20 - 50% of water or aqueous phase.
  • the fatty phase consists, in particular, hydrocarbons, for example vaseline, paraffin oil or hard paraffin's, which preferably comprise suitable hydroxy compounds, such as fatty alcohol's or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax, to improve the water-binding capacity.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate.
  • Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • Fatty ointments are anhydrous and comprise, as the base, in particular, hydrocarbons, for example paraffin, vaseline or paraffin oil, and furthermore naturally occurring or semisynthetic fats, for example hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/or distearate, and for example, the fatty alcohols. They also contain emulsifiers and/or additives mentioned in connection with the ointments which increase uptake of water.
  • hydrocarbons for example paraffin, vaseline or paraffin oil
  • furthermore naturally occurring or semisynthetic fats for example hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/or di
  • Creams are oil-in-water emulsions, which comprise more than 50% of water.
  • Oily bases used are, in particular, fatty alcohols, for example lauryl, cetyl or stearyl alcohols, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example vaseline (petrolatum) or paraffin oil.
  • Emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty esters (Tweens), and furthermore polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl stearyl alcohol or stearyl alcohol.
  • corresponding nonionic emulsifiers for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene
  • Additives to the aqueous phase are, inter alia, agents which prevent the creams from drying out, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, and furthermore talc and/or aluminium silicates, which have the task of binding the moisture or secretions present.
  • metal oxides for example titanium oxide or zinc oxide
  • talc and/or aluminium silicates which have the task of binding the moisture or secretions present.
  • Foams are administered from pressurised containers and they are liquid oil-in-water emulsions present in aerosol for.
  • halogenated hydrocarbons such as chlorofluoro-lower alkanes, for example dichlorofluoromethane and dichlorotetrafluoroethane, or, preferably, non-halogenated gaseous hydrocarbons, air, N 2 O, or carbon dioxide are used.
  • the oily phases used are, inter alia, those mentioned above for ointments and creams, and the additives mentioned there are likewise used.
  • Tinctures and solutions usually comprise an aqueous-ethanolic base to which, humectants for reducing evaporation, such as polyalcohols, for example glycerol, glycols and/or polyethylene glycol, and re-oiling substances, such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture to substitute the fatty substances removed from the skin with the ethanol, and, if necessary, other excipients and additives, are admixed.
  • humectants for reducing evaporation such as polyalcohols, for example glycerol, glycols and/or polyethylene glycol
  • re-oiling substances such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture to substitute the fatty substances removed from the skin with the ethanol, and, if necessary, other excipients and additives, are
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials for administering the composition and may be solid, liquid or gaseous materials, which are inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • the invention also relates to a process or method for treatment of the disease states mentioned above.
  • the compounds can be administered prophylactically or therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount, which is effective against the diseases mentioned.
  • a warm-blooded animal for example a human, requiring such treatment, the compounds are used, in particular, in the form of pharmaceutical composition.
  • a daily dose of about 0.1 to about 5 g, preferably 0.5 g to about 2 g, of a compound of the present invention is administered here for a body weight of about 70 kg.
  • 6-Phenylamino-2-(3-aminopropylamino)-9-isopropyl-9-benzylaminopurine prepared from appropriate 8-bromo derivative, was dissolved in glacial acetic acid. To this solution, 50 mg Pd/BaSO 4 (10 %) was added and the mixture hydrogenated to constant consumption of hydrogen (2 hours). The catalyst was removed by centrifugation and acetic acid was evaporated in vacuo . The rest was purified by column chromatography (silica gel, chloroform-MeOH-conc. NH 4 OH (95 : 5 : 1). Yield 75 %. MS-ESI (+) m/z 340.5 [M+H] +
  • 6-(4-Methoxybenzylamino)-2,8-bis(3-hydroxypropylamino)purine (0.07 mmol) was stirred in 2 mL dimethylformamide with 0.14 mmol of isopropylbromide and with 0.36 mmol of dry potassium carbonate at ambient temperature (6 hours). The solvent was evaporated to dryness and the rest extracted between ethylacetate - water. The organic layer was dried, ethylacetate was evaporated and the rest purified by column chromatograpy (silica gel, chloroform). Yield 55%.
  • 6-chloropurine 1 mmol was alkylated with isopropylbromide in DMF as described in Example 5.
  • the product, 6-chloro-9-isopropylpurine was brominated in acetic acid similarly as described in Example 1.
  • 6-benzylamino-9-isopropyl-8-bromopurine was treated with 2-aminoethanol to give 6-benzylamino-8-hydroxyethylamino-9-isopropylpurine. Yield 40 %.
  • 6-Amino-2-(3-hydroxypropylamino)-9-methyl-8-(3-hydroxypropyloxy)purine was brominated in the position 6 with amylnitrite/CH 2 Br 2 .
  • the 6-bromo derivative was then hydrogenolyzed with PdO/BaSO 4 in strong alkaline solution to give 2,8,9-trisubstituted purine.
  • the crude product was purified by column chromatography (silica gel, chloroform-MeOH-conc. NH 4 OH (8 :2 : 0.2)). The total yield was 35 %.
  • Example 8 1.1 mmol of 7-Hydroxy-1-methyl-3-isopropylpyrazolo[4,3]pyrimidine ( Example 8 ) was dissolved in the mixture of 0.12 mL of dimethylformamide and 5 mL dry chloroform. 11 mmol of thionylchloride (0.81 mL) was added and the solution heated to 80 °C for 1 hour. A new portion of 0.8 mL of thionylchloride and more chloroform-dimethylformamide were then added and heating continued for 3 hours. The solvents were evaporated in vacuo and the rest partitioned between water-chloroform. The organic extract was dried and used in next reaction without purification.
  • 6-(Benzylamino)-2,8-dichloropurine prepared from 2,6,8-trichloropurine, m.p.220-223°C, 50 % yield, was dissolved in 2-aminobutanol and heated to 150°C for 12 hours. After evaporation of the solvent in vacuo the product, 6-benzylamino-2-[(1-hydroxymethyl)propylamino]-8-chloropurine was purified by column chromatography (silica gel, chloroform - MeOH - conc. NH 4 OH 9 : 1 : 0.1) with total yield 36 %. MS-ESI(+) m/z 348 [M+H] + .
  • Freeze-dried epoxy activated Sepharose 6B (Pharmacia LKB, Piscataway, NJ) was chosen for the coupling reaction due to its ability to form an ether bond between a hydroxyl-containing ligand and the epoxide group on the Sepharose.
  • the Sf9 insect cell lysate (500 ⁇ g protein in 1-ml reaction buffer) was passed over the affinity column matrix sequentially five times and the flow through was saved (unbound material). The matrix was then washed three times with 1 ml reaction buffer (wash 1-3) then three times each reaction buffer containing 0.5M NaCI (eluate 1-3).
  • the coupled proteins were eluted at low pH (pH 4.0, 0.1M acetate, 0.5M NaCl) as described above and aliquots (20 ⁇ l from 1 ml) of each sample were assayed for their ability to phosphorylate histone H1 and other substrate proteins as described in Example 12. The presence of CDK complexes was also determined by SDS-PAGE.
  • Cyclin-dependent kinases (p34 cdc2 , p33 cdk2 , p33 cdk4 ) and cyclins (cyclin B, E and D1) are produced in Sf9 insect cells coinfected with appropriate baculoviral constructs.
  • the cells are harvested 68-72 hrs post infection in lysis buffer for 30 min on ice and the soluble fraction is recovered by centrifugation at 14.000 g for 10 min.
  • the protein extract is stored at -80 °C.
  • Rb-GST is produced using an E. coli expression system, containing sequence encoding C terminus of retinoblastoma protein (aminoacids 773-928), which is known to be phosphorylated by p33 cdk4 kinase.
  • the fusion protein is purified on glutathione-agarose beads.
  • Lysis buffer 50mM Tris pH 7,4, 150mM NaCI, 5mM EDTA, 20mM NaF, 1%Tween, 1mM DTT, 0,1mM PMSF, leupeptine, aprotonine
  • the final point test system for kinase activity measurement is used.
  • the kinase is added to reaction mixture in such a way as to obtain linear activity with respect to the concentration of enzyme and with respect to time.
  • the p34 cdc2 and p33 cdk2 kinase inhibition determination involves the use of 1mg/ml histone H1 (Sigma, type III-S) in the presence of 15 ⁇ M [ ⁇ - 32 P]ATP (500-100 cpm/pmol) (Amersham) in a final volume of 20 ⁇ l, inhibition of p33 cdk4 kinase is determined with Rb-GST (0,2mg/ml) as a substrate.
  • Kinase activity is determined at 30 °C in the kinase buffer.
  • Tested compounds are usually dissolved to 100mM solutions in DMSO, final concentration of DMSO in reaction mixture never exceeds 1%.
  • the controls contain suitable dilutions of DMSO.
  • kinase activity is expressed as a percentage of maximum activity, the apparent inhibition constants are determined by graphic analysis.
  • Kinase buffer 50mM Hepes pH 7,4, 10mM MgCl 2 , 5mM EGTA,10mM 2-glycerolphosphate, 1mM NaF, 1mM DTT Kinase Inhibitory Activity of 2,6,8,9-Tetrasubstituted Purine Derivatives SUBSTITUENT CDC2 I ⁇ B- ⁇ C2 N6 C8 N9 IC 50 ( ⁇ M) IC 50 ( ⁇ M) 2-hydroxyethylamino OLOMOUCINE benzylamino - methyl 7 15.4 2-hydroxyethylamino benzylamino fluoro methyl 4.2 7.8 2-hydroxyethylamino benzylamino bromo methyl 16.2 22.8 2-hydroxyethylamino benzylamino mercapto methyl 22.4 35.7 2-hydroxyethylamino benzylamin
  • Metaphase-arrested Xenopus egg extracts were prepared as described previously by Blow “J.Cell Biol.” 122:993 (1993) and stored in liquid nitrogen. Demembranated Xenopus sperm nuclei were prepared as described by Blow & Laskey “Cell” 47:577 (1986). After thawing, extracts were supplemented with 25 mM phosphocreatine, 5 ⁇ g/ml creatine phosphokinase, 250 ⁇ g/ml cycloheximide, [ ⁇ - 32 P]dATP (for DNA synthesis assays).
  • Demembranated sperm nuclei were added to a final sperm concentration of 3 ng/ ⁇ l DNA extract and CDK inhibitor tested was then added at different concentrations. M-phase promoting factor inhibition by different CDK inhibitors was monitored 1.5 h after addition by assessing the amount of sperm nuclei that had been assembled into interphase nuclei, possessing a complete phase-dense nuclear envelope. DNA synthesis was assessed by releasing extract into interphase by the addition of 0.3 mM CaCl 2 and measuring the total amount of [ ⁇ - 32 P]dATP incorporation after 3 h by TCA co-precipitation.
  • a microtiter assay which uses the tetrazolium salt MTT, is now widely used to quantitate cell proliferation and cytotoxicity. For instance, this assay is used in drug screening programs and in chemosensitivity testing. Because only metabolically active cells cleave tetrazolium salts, these assays detect viable cells exclusively.
  • MTT assay yellow soluble tetrazolium salt is reduced to coloured water-insoluble formazan salt. After it is solubilized, the formazan formed can easily and rapidly be quantified in a conventional ELISA plate reader at 570 nm (maximum absorbance). The quantity of reduced formazan corresponds to number of vital cells in the culture.
  • Human T-lymphoblastic leukemia cell line CEM promyelocytic HL-60 and monocytic U937 leukemias; breast carcinoma cell lines MCF-7, BT549, MDA-MB-231; glioblastoma U87MG cells; cervical carcinoma cells HELA; sarcoma cells U2OS and Saos2; hepatocellular carcinoma HepG2; mouse fibroblasts NIH3T3; mouse immortalized bone marrow macrophages B2.4 and B10A.4; P388D1 and L1210 leukemia; B16 and B16F10 melanomas were used for routine screening of compounds.
  • the cells were maintained in Nunc/Corning 80 cm 2 plastic tissue culture flasks and cultured in cell culture medium (DMEM with 5 g/l glucose, 2mM glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 10% fetal calf serum and sodium bicarbonate).
  • DMEM cell culture medium
  • the cell suspensions that were prepared and diluted according to the particular cell type and the expected target cell density (2.500-30.000 cells per well based on cell growth characteristics) were added by pipette (80 ⁇ l) into 96/well microtiter plates. Inoculates were allowed a pre-incubation period of 24 hours at 37°C and 5% CO 2 for stabilisation. Four-fold dilutions of the intended test concentration were added at time zero in 20 ⁇ l aliquots to the microtiter plate wells. Usually, test compound was evaluated at six 4-fold dilutions. In routine testing, the highest well concentration was 266.7 ⁇ M, but it can be the matter of change dependent on the agent. All drug concentrations were examined in duplicates.
  • Incubations of cells with the test compounds lasted for 72 hours at 37°C, in 5% CO 2 atmosphere and 100% humidity.
  • the cells were assayed by using the MTT.
  • Ten microliters of the MTT stock solution were pipetted into each well and incubated further for 1-4 hours.
  • the optical density (OD) was measured at 540nm with the Labsystem iEMS Reader MF (UK).
  • the TCS 50 value the drug concentration lethal to 50% of the tumour cells, was calculated from the obtained dose response curves.
  • EXAMPLE 15 Novel Compounds Induce Apoptosis in Tumour Cells.
  • apoptosis produces little or no inflammation, since the neighbouring cells, especially macrophages, rather than being released into the extracellular fluid, engulf shrunken portions of the cell. In contract, in necrosis, cellular contents are released into the extracellular fluid, and thus have an irritant affect on the nearby cells, causing inflammation.
  • apoptotic cells exhibit shrinkage and blebbing of the cytoplasm, preservation of structure of cellular organelles including the mitochondria, condensation and margination of chromatin, fragmentation of nuclei, and formation of apoptotic bodies, thought not all of these are seen in all cell types.
  • HL-60 cell line was cultured in 6-well culture plates with or without 70 ⁇ M concentration of novel derivatives at 37°C and 5% CO 2 for 3-24 hours. Following the incubation, cells were pelleted, washed in Hank's buffered salt solution and processed as described below.
  • lymphocytes One of the most important parameters of specific cellular immunity is proliferative response of lymphocytes to antigens or polyclonal mitogens.
  • Majority of normal mammalian peripheral lymphocytes is resting cells.
  • Antigens or nonspecific - polyclonal mitogens have capacity to activate lymphoid cells and it is accompanied with dramatic changes of intracellular metabolism (mitochondrial activity, protein synthesis, nucleic acids synthesis, formation of blastic cells and cellular proliferation).
  • Compounds with ability to selectively inhibit lymphocyte proliferation are potent immunosuppressants. Variety of in vitro assays were developed to measure proliferative response of lymphocytes. The most commonly used is 3 H-thymidine incorporation method.
  • Human heparinized peripheral blood was obtained from healthy volunteers by cubital vein punction. The blood was diluted in PBS (1:3) and mononuclear cells were separated by centrifugation in Ficoll-Hypaque density gradient (Pharmacia, 1.077 g/ml) at 2200 g for 30 minutes. Following centrifugation, lymphocytes were washed in PBS and resuspended in cell culture medium (RMPI 1640, 2mM glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 10% fetal calf serum and sodium bicarbonate).
  • RMPI 1640 2mM glutamine
  • penicillin 100 ⁇ g/ml streptomycin
  • 10% fetal calf serum and sodium bicarbonate 10% fetal calf serum and sodium bicarbonate
  • the cells were diluted at target density of 1.100.000 cells/ml were added by pipet (180 ⁇ l) into 96/well microtiter plates. Four-fold dilutions of the intended test concentration were added at time zero in 20 ⁇ l aliquots to the microtiter plate wells. Usually, test compound was evaluated at six 4-fold dilutions. In routine testing, the highest well concentration was 266.7 ⁇ M. All drug concentrations were examined in duplicates. All wells with exception of unstimulated controls were activated with 50 ⁇ l of concanavalin A (25 ⁇ g/ml). Incubations of cells with test compounds lasted for 72 hours at 37°C, in 5% CO 2 atmosphere and 100% humidity. At the end of incubation period, the cells were assayed by using the [ 3 H]-TdR:
  • ED immunosuppressant
  • the activity of the compounds against HIV-1 and HIV-2 induced cytopathicity was examined in human lymphocyte MT-4 cells.
  • the cells 300 000 cells/ml were infected with 100 CCID 50 (1 CCID 50 is a virus quantity which causes cytopathicity effect in 50% of the cells under the experimental conditions) of HIV-1 or HIV-2 and added to 200 ⁇ l wells of a microtiter plate containing different dilutions of the tested compounds.
  • the infected cell cultures were incubated at 37°C for 5 days in a humidified CO 2 incubator.
  • the cytopathicity of the virus was examined by determination of MT-4 cell viability by trypan blue dye staining. The results are summarised in Table 8 with comparison on the prototype compounds.
  • Table 8 also shows the results of activity testing of novel compounds against MSV-induced transformation in murine embryo fibroblast C3H/3T3 cells.
  • the cells were seeded in lml wells of 48-well plates and exposed to 80 PFU (plague forming units) for 60 - 90 min. The virus was subsequently removed and culture medium containing appropriate concentrations of the tested compounds was added (1 ml per well). At day 6-post infection, MSV-induced transformation of the cell culture was examined microscopically.
  • Antiretroviral Activity of Purine Compounds, wherein R9 is either PMP (2-phosphonomethoxypropyl)group or PME (2-phosphonomethoxyethyl)group. ( ⁇ g/ml), (R2 NH 2 ).
  • composition Active ingredient 1250 g
  • Talc 180 g
  • Wheat starch 120 g
  • Magnesium stearate 80 g Lactose 20 g
  • Preparation process The powdered substances mentioned are pressed through a sieve of mesh width 0.6 mm. Portions of 0.33 g of the mixture are transferred to gelatine capsules with the aid of a capsule-filling machine.
  • Preparation process The powdered active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefossé S.A., Saint Priest, France) and ground in a wet-pulveriser to a particle size of about 1 to 3 ⁇ m. Portions of in each case 0.419 g of the mixture are then transferred to soft gelatine capsules by means of a capsule-filling machine.
  • Lauroglykol® propylene glycol laurate, Gattefossé S.A., Saint Priest, France
  • Preparation process The powdered active ingredient is suspended in PEG 400 (polyethylene glycol of Mr between 380 and about 420, Sigma, Fluka, Aldrich, USA) and Tween® 80 (polyoxyethylene sorbitan monolaurate, Atlas Chem. Inc., USA, supplied by Sigma, Fluka, Aldrich) and ground in a wet-pulveriser to a particle size of about 1 to 3 mm. Portions of in each case 0.43 g of the mixture are then transferred to soft gelatine capsules by means of a capsule-filling machine.
  • PEG 400 polyethylene glycol of Mr between 380 and about 420, Sigma, Fluka, Aldrich, USA
  • Tween® 80 polyoxyethylene sorbitan monolaurate, Atlas Chem. Inc., USA, supplied by Sigma, Fluka, Aldrich

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Claims (17)

  1. Dérivés azotés hétérocycliques substitués à la formule I
    Figure 01030001
    où
    A est un groupe divalent à la structure
    Figure 01030002
    Z est N;
    R2 et R6 sont indépendants l'un de l'autre et représentent les halogène, alkyle, alkyle substitué, cycloalkyle, cycloalkyle substitué, cycloalkyle alkyle, arylalkyle, hétéroalkyle, hétéroarylalkyle, cyclohétéroalkyle alkyle ou R6'-X, où
    X est un groupe -NH-, -N(C1-C6-alkyle)-, -O- ou -S-;
    R6' est H, alkyle, alkyle substitué, acyle, amido, sulfo, cycloalkyle, cycloalkyle substitué, aryle, aryle substitué, hétérocycle, hétéroalkyle, hétéroalkyle substitué, arylalkyle, cyclohétéroalkyle, cyclohétéroalkyle substitué, hétéroarylalkyle, hétéroalkyle, cycloalkyle alkyle et cyclohétéroalkyle alkyl;
    R8 est halogène, hydroxyle, amino, carboxyle, cyano, nitro, amido, sulfo, sulfamido, carbamino, alkyle, alkyle substitué, cycloalkyle, cycloalkyle substitué, arylalkyle, hétéroalkyle, hétéroarylalkyle, cycloalkyle alkyle, cyclohétéroalkyle alkyl ou R8'-X, où
    X est un groupe -NH-, -N(alkyle)-, -O-, ou -S- et
    R8' est n'importe quel des substituants définis ci-dessus pour R2' ou R6'.
    R9 est : alkyle, alkyle substitué, acyle, carboxyle, amido, sulfamino, cycloalkyle, cycloalkyle substitué, cycloalkyle alkyle, hétéroalkylcycloalkyle alkyle, hétérocycloalkyle, hétérocycloalkyle substitué, aryle, aryle substitué, hétérocycle, hétéroaryle, hétéroaryle substitué, arylalkyle, hétéroarylalkyle, hétéroalkyle ou -B-R9'-, où
    B est un groupe -CH2-, -(CH2)2-, -CH(CH3)CH2-, -CH(CH2F)CH2, -CH(CH2OH)CH2-, ou un groupe à la structure suivante,
    Figure 01040001
    où la liaison sur la partie gauche communique avec l'azote du cycle de composés de 5 membres à la formule I;
    R4 et R5, qui sont indépendants l'un de l'autre, représentent le : hydrogène, hydroxyle, halogène, amino, acyloxy substituant avec 1-5 atomes de carbone, alkoxy substituant avec 1-5 atomes de carbone, alkylmercapto substituant avec 1-5 atomes de carbone, alkylamino substituant avec 1-5 atomes de carbone et dialcolamino groupe, où chaque substituant alcoylé a 1-5 atomes de carbone;
    R7 et R10, qui sont indépendants l'un de l'autre, représentent H ou l'alkyle avec 1-10 atomes de carbone;
    R9 est un groupe -(CH2)n-R9', où n = 1-2 et
    R9' est un groupe -X(CH2)mY, où
    X est -O-, -S-, -NH-, ou -N(alkyle)- substituant avec 1-6 atomes de carbone;
    m = 1-2;
    Y est : carboxyle, amido, sulfo, sulfamino, hydroxyle, carboxyle, mercapto, carbylmercapto, amino, alkylamino, carbamino, -PO(OH)2, -PO(O-C1-C6-alkyl)2, -PO(NH-C1-C6-alkyle)2, -PO(O-C1-C6-alkyle)(NH-C1-C6-alkyle), -PO(OH)(O-C1-C6-alkyle);
    -PO(OH)(NH-C1-C6-alkyle) ou
    -(CH2CHD)-R9', où
    R9', X, m et Y sont définis ci-dessus et
    D est : alkyle, alkyle substitué, -PO(OH)2, -PO(OH)(O-C1-C6-alkyle), -PO(OH)(NH-C1-C6-alkyle),
    où les groupes généraux jusqu'ici non définis ont la signification indiquée dans la légende suivante :
    "halogène"
    signifie l'atome de fluor, brome, chlore et iode;
    "alkyle"
    signifie
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone;
    "alkyle substitué"
    signifie un groupe arborescent ou non arborescent alkylé, alkenylé ou alkinylé avec 1 -6 atomes de carbone, substitué par un ou plusieurs substituants sélectionnés du groupe consistant de hydroxyle, mercapto, carbylmercapto, halogène, carbyloxy, amino, amido, carboxyle, cycloalkyle, sulfo, ou acyle, ces groupes généraux de substituants ont la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "carbyloxy"
    signifie le groupe -ORa, où Ra est : alkyle, alkyle substitué, aryle, aryle substitué, arylalkyle, arylalkyle substitué, cycloalkyle, cycloalkyle substitué, hétérocycloalkyle ou hétérocycloalkyle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende; "carbylmercapto"
    signifie le groupe -SRb, où Rb est : alkyle, alkyle substitué, aryle, aryle substitué, arylalkyle, arylalkyle substitué, cycloalkyle, cycloalkyle substitué, hétérocycloalkyle ou hétérocykloalkyle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende; "sulfo"
    signifie le groupe -SO3Rc, où Rc est
    hydrogène,
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone,
    un groupe alkylé, alkenylé ou alkinylé arborescent ou non arborescent avec 1 -6 atomes de carbone qui est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de hydroxyle, mercapto, carbylmercapto, halogène, carbyloxy, amino, amido, carboxyle, cycloalkyle, sulfo ou acyle, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende; "sulfamino"
    signifie le groupe -NHSO3Rd, où Rd est
    hydrogène,
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone,
    un groupe alkylé, alkenylé ou alkinylé arborescent ou non arborescent avec 1 -6 atomes de carbone qui est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de hydroxyle, mercapto, carbylmercapto, halogène, carbyloxy, amino, amido, carboxyle, cycloalkyle, sulfo ou acyle, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende; "acyl"
    signifie le groupe -C(O)Re, où Re est : hydrogène, alkyle, alkyle substitué, aryle, aryle substitué, arylalkyle, arylalkyle substitué, cycloalkyle, cycloalkyle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "aryloxy"
    signifie le groupe -OAr, où Ar est : aryle, aryle substitué, hétéroaryle ou hétéroaryle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "alkylamino"
    signifie le groupe -NRfRg, où Rf et Rg, qui sont indépendants l'un de l'autre, représentent :
    hydrogène, alkyle, alkyle substitué, aryle, aryle substitué, hétéroaryle ou hétéroaryle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "amido" signifie le groupe -C(O)NRhRi', où Rh et Ri' peuvent être indépendamment hydrogène, alkyle, alkyle substitué, aryle, aryle substitué, hétéroaryle, hétéroaryle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "karboxyl"
    signifie le groupe -C(O)ORj, où Rj est : hydrogène, alkyle, alkyle substitué, aryle, aryle substitué, hétéroaryle ou hétéroaryle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "carbamino"
    signifie le groupe -NHCORk, où Rk peut être: hydrogène, alkyle, alkyle substitué, hétérocycle, aryle, aryle substitué, hétéroaryle et hétéroaryle substitué, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "aryle"
    signifie un groupe aromatique carbocyclique avec 1 à 18 atomes de carbone, qui est composé d'au moins un cycle aromatique ou de multiples cycles condensés, dont au moins un est aromatique;
    "aryle substitué"
    signifie un groupe aromatique carbocyclique avec 1 à 18 atomes de carbone, qui est composé d'au moins un cycle aromatique ou de multiples cycles condensés, dont au moins un est aromatique, ce(s) cycle(s) sont substitué de façon optionnelles par un ou plusieurs substituants sélectionnés du groupe consistant de : halogène, alkyle, hydroxyle, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyle, nitro, mercapto ou sulfo groupes, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "hétérocycle"
    signifie un groupe hétérocyclique avec 4 à 9 atomes de carbone et avec au moins un hétéroatome sélectionné du groupe consistant de N, O ou S;
    "hétéroaryle"
    signifie un groupe hétérocyclique avec 4 à 9 atomes de carbone et avec au moins un hétéroatome sélectionné du groupe consistant de N, O ou S, où au moins un cycle de ce groupe est aromatique;
    "hétéroaryle substitué"
    signifie un groupe hétérocyclique avec 4 à 9 atomes de carbone et avec au moins un hétéroatome sélectionné du groupe consistant de N, O ou S, où au moins un cycle de ce groupe est aromatique et ce groupe est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, carbyloxy, carbylmercapto, alkylamino, amido, carboxyle, hydroxyle, nitro, mercapto, ou sulfo groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "arylalkyle"
    signifie le groupe -R1-Ar, où R1 est
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone,
    et Ar est
    un groupe aromatique carbocyclique avec 1 à 18 atomes de carbone, qui est composé d'au moins un cycle aromatique ou de multiples cycles condensés, dont au moins un est aromatique et le groupe est substitué de façon optionnelle par un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, hydroxyle, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyle, nitro, mercapto ou sulfo groupe, ces
    groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "hétéroalkyle" signifie le groupe -Rm-L, où L est
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkylé, alkenylé ou alkinylé avec 1 -6 atomes de carbone, qui est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de hydroxyle, mercapto, carbylmercapto, halogène, carbyloxy, amino, amido, carboxyle, cycloalkyle, sulfo ou acyle groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende
    et L est
    un groupe hétérocyclique avec 4 à 9 atomes de carbone et au moins un hétéroatome sélectionné du groupe consistant de N, O ou S et le groupe est non substitué ou substitué par un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, alkoxy, alkylmercapto, alkylamino, amido, carboxyle, hydroxy, nitro, mercapto ou sulfo groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "hétéroarylakyle"
    signifie le groupe -Rn-G-, où Rn est
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkylé, alkenylé ou alkinylé avec 1 -6 atomes de carbone, qui est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de hydroxyle, mercapto, carbylmercapto, halogène, carbyloxy, amino, amido, carboxyle, cycloalkyle, sulfo ou acyle groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende
    et G est
    un groupe hétérocyclique avec 4 à 9 atomes de carbone et avec au moins un hétéroatome sélectionné du groupe consistant de N, O ou S, avec au moins un cycle qui est aromatique, et le groupe est substitué de façon optionnelle par un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, carbyloxy, carbylmercapto, alkylamino, amido, carboxyle, hydroxyle, nitro, mercapto ou sulfo groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "cycloalkyle"
    signifie un groupe alkylé monocyclique ou polycyclique consistant de 3 à 15 atomes de carbone;
    "cycloalkyle substitué"
    signifie un groupe alkylé monocyclique ou polycyclique consistant de 3 à 15 atomes de carbone, qui est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, alkyle substitué, carbyloxy, carbylmercapto, aryle, nitro, mercapto ou sulfo groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende; "hétérocycloalkyle"
    signifie un groupe alkylé monocyclique ou polycyclique consistant de 3 à 15 atomes de carbone, où au moins un atome de carbone dans le cycle de sa structure cyclique est remplacé par un hétéroatome sélectionné du groupe consistant de N, O, S ou P;
    "hétérocycloalkyle substitué"
    signifie un groupe alkylé monocyclique ou polycyclique consistant de 3 à 15 atomes de carbone, où au moins un atome de carbone dans le cycle de sa structure cyclique est remplacé par un hétéroatome sélectionné du groupe consistant de N, O, S ou P et le groupe contient un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, alkyle substitué, carbyloxy, carbylmercapto, aryle, nitro, mercapto ou sulfo groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende;
    "cycloalkyle alkyle"
    signifie le groupe -Ro-J, où Ro est
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkylé, alkenylé ou alkinylé avec 1 -6 atomes de carbone, qui est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de hydroxyle, mercapto, carbylmercapto, halogène, carbyloxy, amino, amido, carboxyle, cycloalkyle, sulfo ou acyle groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende
    et J est
    un groupe alkylé monocyclique ou polycyclique contenant 3 à 15 atomes de carbone;
    un groupe alkylé monocyclique ou polycyclique contenant 3 à 15 atomes de carbone, qui contient un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, alkyle substitué, carbyloxy, carbylmercapto, aryle, nitro, mercapto ou sulfo groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende; et
    "hétérocycloalkylalkyle"
    signifie le groupe -RpV, où Rp est
    un groupe arborescent ou non arborescent alkylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkenylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkinylé avec 1-6 atomes de carbone,
    un groupe arborescent ou non arborescent alkylé, alkenylé ou alkinylé avec 1 -6 atomes de carbone, qui est substitué par un ou plusieurs substituants sélectionnés du groupe consistant de hydroxyle, mercapto, carbylmercapto, halogène, carbyloxy, amino, amido, carboxyle, cycloalkyle, sulfo ou acyle groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende
    et V est
    un groupe alkylé monocyclique ou polycyclique contenant 3 à 15 atomes de carbone, où au moins un est remplacé par un hétéroatome sélectionné du groupe consistant de N, O, S ou P;
    un groupe alkylé monocyclique ou polycyclique contenant 3 à 15 atomes de carbone, où au moins, et le groupe contient un ou plusieurs substituants sélectionnés du groupe consistant de halogène, alkyle, alkyle substitué, carbyloxy, carbylmercapto, aryle, nitro, mercapto ou sulfo groupe, ces groupes généraux de substituants ayant la signification identique aux définitions des groupes correspondants, tels que définis dans cette légende
    sous condition que
    a) R9 ne soit pas un benzyle ou benzyle substitué
    b) R8 ne soit pas un aryle, aryle substitué, cycloalkyle, cycloalkyle substitué, hétéroaryle, ou hétéroaryle substitué, alkenyle ou alkenyle substitué
    c) R8 ne soit OH, SH, acyloxy et acyloxy substitué
    et leurs sels d'acide acceptables au point de vue pharmaceutique, racémates et isomères optiques.
  2. Dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule Ib,
    Figure 01110001
    où R2, R6, R8 et R9 sont définis ci-dessus à la revendication 1.
  3. Les dérivés azotés hétérocycliques substitués à la formule I selon la revendication 1, sélectionnés du groupe consistant de 2-(1-hydroxyméthylpropylamino)-6-benzylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-karboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-(2-aminopropylamino)-6-benzylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-(2-hydroxypropylamino)-6-benzylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-diéthylamino-6-(4-méthoxybenzylamino)-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-(2-hydroxypropylamino)-6-(3-chloranilino)-8-chlor (ou hydroxy, brome, amino, C1-C6 alkyle, méthyle, éthyle, propyle, isopropyle, vinyle, allyle, propargyle)-9-isopropylpurine, 2-(2-hydroxypropylamino)-6-(3-chlor-4-carboxyanilino)-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-(R)-(2-hydroxypyrrolidine-1-yl)-6-benzylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-(R)-(1-isopropyle-2-hydroxyéthylamino)-6-(3-chlore-4-carboxyanilino)-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-(R)-(1-isopropyle-2-hydroxyéthylamino)-6-benzylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-ammoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-(R)-(1-isopropyle-2-hydroxyéthylamino)-6-(3-chloranilino)-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-isopropylpurine, 2-alkylamino-6-diméthylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhyoxypropyle)-purine, 2-alkylamino-6-diéthylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhoxypropyle)purine, 2-akylamino-6-butylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhoxypropyle)purine, 2-alkylamino-6-(2-butylamino)-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhoxypropyle)purine, 2-alkylamino-6-cyklopropylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-karboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhoxypropyle)purine, 2-amino-6-cyclohexylamino-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhoxypropyle)purine, 2-alkylamino-6-(pyrrolidine-1-yl)-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhoxypropyle)purine, 2-alkylamino-6-(morfoline-1-yle)-8-chlore (ou hydroxy, brome, fluor, amino, amido, carboxy, cyano, méthylamino, thio, méthylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-phosphonoalkylamino, ω-phosphonoalkyloxy, propinyle)-9-(R)-(2-phosphonométhoxypropyle)purine.
  4. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I, où R2, R6, R8 et R9 sont définis dans la revendication 1, A est un groupe à la formule
    Figure 01130001
    et Z est N, caractérisé par le fait, que le dérivé trisubstitué à la formule XI,
    Figure 01130002
    où R2, R6 et R9 sont définis dans la revendication 1, est bromé à l'aide d'un système de bromuration sélectionné d'un groupe consistant du brome/acide acétique, brome/chloroforme, brome/agent régulateur d'acétate, brome/eau, N-bromsuccinimide/diméthylformamide et bromacetamide/diméthylformamide de manière à obtenir un dérivé à la formule XIa,
    Figure 01140001
    où R2, R6 et R9 sont définis à la revendication 1, et l'atome de brome dans la position 8 du dérivé à la formule XIa est ensuite de façon optionnelle soumis à la substitution nucléophile pour être remplacé par un autre substituant R8 défini à la revendication 1.
  5. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I, où R2, R6, R8 et R9 sont définis dans la revendication 1, A est un groupe à la formule
    Figure 01140002
    et Z est N, caractérisé par le fait que le dérivé trisubstitué à la formule XIb,
    Figure 01140003
    où R6 et R9 sont définis dans la revendication 1, est bromé à l'aide d'un système de bromuration sélectionné d'un groupe consistant du brome/acide acétique, brome/chloroforme, brome/agent régulateur d'acétate, brome/eau, N-bromsuccinimide/diméthylformamide et bromacetamide/diméthylformamide de manière à obtenir un dérivé à la formule XIc,
    Figure 01140004
    où R6 et R9 sont définis dans la revendication 1 et l'atome de chlore dans la position 2 et l'atome de brome dans la position 8 du dérivé à la formule XIc sont de manière optionnelle soit progressivement soit simultanément soumis à la substitution pour être remplacés par d'autres substituants R2 et R8 qui sont définis à la revendication 1.
  6. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la formule I, où R2, R6 et R8 sont définis à la revendication 1, R9 est un alkyle défini à la revendication 1, A est un groupe à la formule
    Figure 01150001
    et Z est N, caractérisé par le fait que le dérivé trisubstitué à la formule XIIa,
    Figure 01150002
    où R6 est défini dans la revendication 1, est alcoylé dans la position 9 à l'aide d'un alcoylant approprié sélectionné du groupe consistant de K2CO3/diméthylformamide,
    Cs2CO3/diméthylformamide, t-BuOK/diméthylformamide, t-BuOK/diméthylsulfoxide et NaH/diméthylformamide ou sous les conditions de la réaction Mitsunobu pour obtenir un dérivé à la formule XIIb,
    Figure 01150003
    où R6 et l'alkyle sont définis dans la revendication 1, et les atomes de chlore dans les positions 2 et 8 du dérivé à la formule XIIb sont de façon optionnelle soit progressivement soit simultanément soumis à la substitution nucléophile de manière à être remplacés par d'autres substituants R2 et R8, définis à la revendication 1.
  7. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la revendication 1, où R2, R6 et R8 sont définis à la revendication 1, R9 est un alkyle défini à la revendication 1, A est un groupe à la formule
    Figure 01160001
    et Z est N, caractérisé par le fait que le dérivé trisubstitué à la formule XIIa,
    Figure 01160002
    où R6 est défini à la revendication 1, est protégé par la réaction, par exemple avec le 2-dihydropyrane/H+ pour obtenir un dérivé à la formule XIIc,
    Figure 01160003
    où R6 est défini à la revendication 1 et le groupe R6 et/ou l'atome de chlore dans la position 2 et/ou l'atome de chlore dans la position 8 sont de manière optionnelle remplacés par d'autres substituants R2, R6 et R8, définis à la revendication 1, et dans chaque produit ainsi modifié de façon optionnelle ayant la formule XIIc, le groupe 2-tetrahydropyranyle est détaché pour obtenir un dérivé correspondant à la formule XIIc, où R9 et un hydrogène et le produit ainsi obtenu est ensuite alcoylé dans la position 9 à l'aide d'un alcoylant approprié dans un système sélectionné du groupe consistant de K2CO3/diméthylformamide, Cs2CO3/diméthylformamide, t-BuOK/diméthylformamide, t-BuOK/diméthylsulfoxide et NaH/diméthylformamide ou sous les conditions de la réaction Mitsunobu pour obtenir un dérivé à la formule XIIc, où R2, R6, R8 et R9 sont définis dans la revendication 1.
  8. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I, où R2, R6 et R8 sont définis à la revendication 1, R9 est un alkyle défini à la revendication 1, A est un groupe à la formule
    Figure 01170001
    et Z est N, caractérisé par le fait que le 2,6,8-trichlorpurine est soumis à la substitution nucléophile dans la position 6 pour que le chlore dans la position 6 soit remplacé par un autre substituant R6 défini à la revendication 1 pour obtenir un dérivé à la formule XIIa,
    Figure 01170002
    où R6 est défini à la revendication 1 et le produit ainsi obtenu est ensuite alcoylé dans la position 9 à l'aide d'un alcoylant approprié dans un système sélectionné du groupe consistant de K2CO3/diméthylformamide, Cs2CO3/diméthylformamide, t-BuOK/diméthylformamide, t-BuOK/diméthylsulfoxide et NaH/diméthylformamide ou sous les conditions de la réaction Mitsunobu pour obtenir un dérivé à la formule XIIb,
    Figure 01170003
    où R6 et l'alkyle sont définis à la revendication 1 et les atomes de chlore dans les positions 2 et 8 du dérivé à la formule XIIb sont de manière optionnelle soit progressivement soit simultanément soumis à la substitution nucléophile pour être remplacés par d'autres substituants R2 et R8, définis à la revendication 1.
  9. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I, où R2, R6 et R8 sont définis à la revendication 1, R9 est un alkyle défini à la revendication 1, A est un groupe à la formule
    Figure 01180001
    et Z est N, caractérisé par le fait que le 2,6-dichlorpurine est soumis à la substitution nucléophile dans la position 6 pour que l'atome de chlore dans la position 6 soit remplacé par un autre substituant R6 défini à la revendication 1 et le dérivé ainsi obtenu à la formule XVII,
    Figure 01180002
    où R6 est défini à la revendication 1, est alcoylé dans la position 9 à l'aide soit de l'acrylate de méthyle, soit du nitril acrylique, soit de l'oxirane pour obtenir un dérivé à la formule XVIIa,
    Figure 01180003
    où R6 et l'alkyle sont définis à la revendication 1 et ce produit est ensuite bromé dans la position 8 à l'aide d'un système de bromuration sélectionné du groupe consistant du brome/acide acétique, brome/chloroforme, brome/agent régulateur d'acétate, brome/eau, N-bromsuccinimide/diméthylformamide et bromacetamide/diméthylformamide de manière à obtenir un dérivé à la formule XVIIb,
    Figure 01190001
    où R6 et l'alkyle sont définis à la revendication 1 et le produit ainsi obtenu est ensuite de manière optionnelle soit progressivement soit simultanément soumis à la substitution nucléophile dans les positions 2 et 8 pour que l'atome de chlore dans la position 2 et l'atome de brome dans la position 8 soient remplacés par d'autres substituants R2 et R8 définis à la revendication 1.
  10. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I, où R6 est un halogène, R2, R8 et R9 sont définis à la revendication 1, A est un groupe à la formule
    Figure 01190002
    et Z est N, caractérisé par le fait que le dérivé à la formule XVIII,
    Figure 01190003
    où R2, R8 et R9 sont définis à la revendication 1, est halogéné à l'aide d'une diazotation avec usage, par exemple, du nitrite d'amyle/CH2Br2 ou du nitrite d'amyle/CH3I.
  11. Procédé pour la préparation des dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I, où R9 est défini à la revendication 1 et un substituant R2, R6 ou R8 est un alkinyle ou alkényle, contenant 1 à 6 atomes de carbone tandis que les deux autres substituants R2, R6 et R8 sont définis à la revendication 1, A est un groupe
    Figure 01200001
    et Z est N ou CH, caractérisé par le fait que le dérivé à la formule I, où R9 est défini à la revendication 1 et l'un des substituants R2, R6 et R8 est un halogène tandis que les deux autres substituants R2, R6 et R8 sont définis à la revendication 1, est alkinylé dans la position de l'halogène à l'aide du système alkine/trifenylfosfine-PdCl2/CuI/triéthylamine et le dérivé 2-, 6-, 8-alkinyle ainsi obtenu est ensuite converti de façon optionnelle en un dérivé 2-, 6- ou 8-alkényle à l'aide du catalyseur de Lindlar.
  12. Dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I et leurs sels acceptables au point de vue pharmaceutique, utilisables comme médicaments.
  13. Dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I utilisables comme moyen pour la préparation des matrices à absorption d'affinité, des enzymes immobilisés pour le contrôle du processus, des réactifs pour l'immunoassay, des échantillons de diagnostic, des composés indiqués 14C, 3H, avidine ou biotine, des oligonucléodites et des échantillons diagnostiques.
  14. Dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I utilisables comme produits antimiotiques, notamment les produits pour l'élimination ou la réduction de la propagation des virus ou de leur croissance dans les systèmes à culture de tissu pendant la préparation des produits biopharmaceutiques ou d'autres produits comme les protéines et vaccins, les produits pour l'élimination ou la réduction de la propagation des virus ou de leur croissance dans les échantillons cliniques tels que le sang et les produits pour l'arrêt de la croissance des cellules dans les cultures de tissu, tandis que les cellules continuent à produire les protéines.
  15. Composition pharmaceutiques ayant une activité cytostatique, anticancéreuse, antimiotique, antineurodégénérative, immunosuppressive et antimicrobiale, caractérisés par le fait qu'ils contiennent en dehors des produits pharmaceutiques auxiliaires au moins un dérivé azoté hétérocyclique substitué selon la revendication 1 à la formule I.
  16. Compositiont pharmaceutique combiné à effet cytostatique, caractérisé par le fait qu'il contient en dehors des produits pharmaceutiques auxiliaires au moins un dérivé azoté hétérocyclique substitué selon la revendication I et un agent cytostatique sélectionné du groupe consistant de mitoxantrone, cis- et carbo-platine, méthotrexate, taxol et doxorubicine.
  17. L'utilisation des dérivés azotés hétérocycliques substitués selon la revendication 1 à la formule I pour la préparation des médicaments destinés pour le traitement des tumeurs, cancers, psoriasis, arthrite rhumatisante, lupus, diabète du type I, sclérose en plaques, restenosis, maladie polycyclique rénale, maladie du hôte évoqué par le tissu transplanté (host graft disease) et goutte, parasitoses qui sont causées par les fongus ou prostis, ou de la maladie d'Alzheimer ou pour la préparation des médicaments antineurodégéneratifs et des agents pour la suppression de l'immunostimulation.
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US6552192B1 (en) 2003-04-22
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